Although tumor-specific immune cells are found in stage IV breast cancer patients, they are not able to control tumor growth. This is in part due to tumor stroma that tightly surrounds tumor nests. Tumor stroma contributes to immune evasion of breast cancer in at least two critical ways; by creating a physical barrier that prevents direct contact between tumor infiltrating immune cells and malignant cells, and by producing immunosuppressive cytokines that directly block activation of immune cells and/or attract/activate immuno-suppressive cells such as regulatory T-cells. In this proposal, we will test a new stem cell gene therapy approach that targets tumor stroma cells with the goal to enable existing immune cells to control tumor growth. The specific tumor microenvironment as well as cytokines/growth factors produced by tumor cells trigger differentiation of tumor-infiltrating hematopoietic tumor cells into a unique type of macrophages (so called tumor-associated macrophages -TAMs), with a gene expression signature that is distinct from that of tissue macrophages and myeloid cells. TAMs are the prevalent stroma cell type and the number of TAMs directly correlates with breast cancer malignancy. Our central hypotheses are that i) bone marrow derived TAM progenitors can be used to deliver therapeutic transgenes to the tumor stroma, ii) the unique mRNA and microRNA expression profile of TAMs can be used to construct TAM-specific transgene expression systems, and iii) that drug controlled, transgene mediated killing of stroma cells and/or degradation of stroma protein enable long-term control of cancer. We provide a series of preliminary data that support the feasibility of our strategy. We will test our hypotheses in a mouse model of breast cancer involving rat neu-transgenic mice (neu-tg) and syngeneic mammary carcinoma cells (MMC). Key findings will be validated in a second breast cancer model that involves 4T1 cells and BALB/c mice.